Early Phase Clinical Trials

Module Code 32207

Assessment brief 2024/2025

Extended Writing: Structured Short-Answer Questions

The assessment consists of three question sections (Section A to Section C). Each section contains a trial scenario and a series of short-answer questions relating to that scenario.

You must answer ALL questions.

The maximum marks available for each question and each section are included in this paper.

This assessment will be scored out of a total of 75 marks and contributes 100% to your final overall module mark.

Submission format:

Please create a Microsoft Word document using font size 11 or 12. If you are unable to create a Word document, please create a pdf file. Ensure the relevant section and question number are included before each answer, but please do not include the full questions.

The name of your document should use the following format ‘EPCT STUDENT-ID’, so if your student ID was 1234567, your filename would be ‘EPCT 1234567’.

Include your Student ID on each page but DO NOT include your name.

Word limit: 2500 words

Assessment weighting: 100% of module mark

Submission deadline: Monday 19^th May 2025, 12:00 midday

Submission is via CANVAS (further details will be provided on CANVAS)

SECTION A: Phase I Trials (25 marks)

Primary Sclerosing Cholangitis (PSC) is an uncommon liver disease in which the bile ducts inside and outside the liver progressively decrease in size due to inflammation and scarring.

Drug X is a new Ileal bile acid transporter (IBAT) inhibitor which is intended to be used in the treatment of PSC. Treatment for PSC must be taken daily and IBAT inhibitors are associated with long-term side-effects which can make compliance (and therefore benefit) poor. It is hoped drug X will have a more favourable side-effect profile. A multi-disciplinary trial team want to know if Drug X can be used to treat PSC and are planning a phase I dose escalation trial. Drug X has never been tested in humans before.

Common side-effects of other, similar IBAT inhibitors include abdominal pain; nausea; vomiting; dizziness; and diarrhoea.

It is anticipated that the side-effects of Drug X will be dose-related (that is, they will increase as the dose increases).

Questions

1. Identify three design or delivery features of the dose escalation trial that could be established to mitigate potential risks for the participants. Describe each feature and explain what risk it is likely to mitigate. (9 marks)

2. The phase I dose escalation trial is conducted, with the maximum tolerated dose (MTD) defined as the dose that gives a target dose-limiting toxicity (DLT) rate of 10%. Figure A below, shows the results of the trial for each participant and whether they experienced a DLT or not. Table A shows output and results for the trial (obtained using dfcrm in R statistical package). State the maximum tolerated dose recommended by the continual reassessment method (CRM)? Justify your answer. (2 marks)

3. At what point in the trial (as illustrated in Figure A) would a 3+3 design (with MTD defined by 1/6) deviate from the path taken by the CRM? Justify your answer. (3 marks)

4. State 3 advantages or disadvantages of the CRM design over a 3+3 design in this scenario? For each, explain the consequence of the advantage/disadvantage. Your answer should refer to data in Table 1 above and the parameters specified in the question. Note, your answer should include 3 advantages or disadvantages (not 3 advantages and 3 disadvantages). (6 marks)

5. Prior to the dose escalation trial described in question 2 above, the research team considered targeting the minimum effective dose, rather than the maximum tolerated dose. Define what is meant by a minimum effective dose and explain why this might be of interest in this scenario. (2 marks)

6. Briefly explain how the dose escalation trial would have differed if the researchers had aimed to determine the minimum effective dose, rather than the maximum tolerated dose. Your answer should consider: (i) outcome measures; (ii) trial design; and (iii) decision making. (3 marks)

Table A: Statistical output (using R)

Figure A: Trial History – Patient Results

SECTION B: Phase II Trials (25 marks)

Juvenile idiopathic arthritis (JIA) is arthritis of unknown cause, diagnosed in childhood, and is the most common rheumatic disease in children. It typically results in warm, swollen, stiff, and painful joints, commonly around the wrist and hands, however it can affect other parts of the body including the skin, eyes, lungs, heart, nerves, and blood. JIA is a rare disease with an estimated incidence of 4-14 cases per 100,000 children annually. A rare side-effect of JIA is uveitis, which is inflammation in the eye that can cause vision loss and blindness. It can affect one or both eyes.

Questions within this section relate to the paper by Ramanan et al., which is available within the Canvas pages. The reference for this paper is also provided below.

Ramanan, AV., Dick, AD., Guly, C., McKay, A., Jones, AP., Hardwick, B., Lee, RWJ., Smyth, M., Jaki, T., Beresford, MW., on behalf of the APTITUDE Trial Management Group. Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial. The Lancet Rheumatology. 2020 Mar; 2(3):E135-E141.

Questions

1. Summarise the trial design employed by Ramanan and colleagues, using the PICOT framework (5 marks)

2. State the null and alternative hypotheses being tested, the statistical error rates associated with each hypothesis, and the decision boundaries. Briefly explain, in your own words, what the authors’ rationale might be behind these design choices. (7 marks)

3. Why do you think the researchers chose a Simons two stage design rather than an A’Hern design? (3 marks)

4. In general, what are the limitations of a Simons two stage design for a single arm phase II trial? (4 marks)

5. In the Ramanan study why might the researchers have chosen a fixed-N design rather than a Bayesian design for their single arm trial? (3 marks)

6. For the primary outcome only, summarise the results presented in the Ramanan paper. Referring to the trial hypotheses, comment on the clinical relevance of the results and the rationale for their choice of confidence interval. (3 marks)

SECTION C: Complex innovative Designs (CID) (25 marks)

Research has shown a number of key genetic mutations present in advanced breast cancer that provide attractive therapeutic opportunities. In particular, some novel targeted therapies have been identified to be potentially beneficial to patients whose advanced breast cancer is progressing after receiving at least one previous line of treatment. Those patients whose tumours have mutations in the oestrogen receptor ESR1 may benefit from a drug called fulvestrant which is a selective oestrogen receptor downregulator; those with HER2 mutations may benefit from a drug called neratinib which is an irreversible pan-HER tyrosine kinase inhibitor; those with AKT1 mutations may benefit from a drug called capivasertib which is a selective AKT inhibitor; and those with PTEN mutations may also benefit from the drug capivasertib.

A team of clinical researchers want to set up a phase II clinical trial with a complex innovative design (CID), to determine whether these different targeted treatments provide benefit to patients with advanced breast cancer whose disease has progressed after receiving one previous line of treatment. The occurrence of an objective response (that is, complete or partial response according to RECIST) is the primary outcome measure.

Questions

1. What type of CID could be used to assess these different targeted drugs in the specific subgroups of patients with advanced breast cancer, in a single protocol? Briefly describe your design and justify your choice. Include a trial schema or flow diagram to aid your description. As a phase II trial, you can assume that the trial will not include any randomised control arms. (6 marks)

2. Considering your CID design in Section C, Question 1, answer the following questions:

(a) State the key research questions (in terms of objective response) that the trial is aiming to answer. (2 marks)

(b) Archival primary tumour tissue collected at the time of the original diagnosis cannot be assumed to be representative of the advanced disease genomic profile present at the time they are eligible for the trial, so fresh tissue biopsies from metastatic disease will be required to genetically test the patients for entry to the trial. Summarise some of the key challenges related to this requirement. (3 marks)

(c) Describe the different options that could be considered for consenting patients whose tumours cannot be genetically categorised because the quality of the tumour sample was not good enough for a valid result. (2 marks)

(d) Describe the different options that could be considered for consenting patients whose tumours are genetically categorised as having no relevant mutations.
(2 marks)

(e) Patients will often have ESR1 mutations (i.e. they are ‘oestrogen-receptor positive’) as well as having either HER2, AKT1 or PTEN mutations. Previous research has shown that it is safe to receive fulvestrant in combination with other targeted drugs. How might the trial design deal with this situation? (3 marks)

3. Suppose that the prevalence of ESR1, HER2, AKT1 and PTEN gene mutations in advanced breast cancer are about 30%, 15%, 5% and 5% respectively.

(a) Discuss how these different prevalences might affect the ability to recruit participants and evaluate the efficacy of the targeted drugs. (3 marks)

(b) If the actual prevalence of each of the different mutations was much lower than expected, at around 1%, then how might this affect the feasibility of the trial?
(1 mark)

4. Describe any adaptive features that could be built into the design to improve the efficiency of the trial. (3 marks)